Mitogen-activated protein kinases (MAP) is a family of proline-directed serine/threonine kinases that activate their substrates by dual phosphorylation. The kinases are activated by a variety of signals, including nutritional and osmotic stress, UV light, growth factors, endotoxin, and inflammatory cytokines. The p38 MAP kinase group is a MAP family of various isoforms, including p38α, p38β, and p38γ. These kinases are responsible for phosphorylating and activating transcription factors (e.g., ATF2, CHOP, and MEF2C), as well as other kinases (e.g., MAPKAP-2 and MAPKAP-3). The p38 isoforms are activated by bacterial lipopolysaccharide, physical and chemical stress, and pro-inflammatory cytokines, including tumor necrosis factor (“TNF”) and interleukin-1 (“IL-1”). The products of the p38 phosphorylation mediate the production of inflammatory cytokines, including TNF, IL-1, and cyclooxygenase-2.
It is believed that p38α kinase can cause or contribute to the effects of, for example, inflammation generally; arthritis; neuroinflammation; pain; fever; pulmonary disorders; cardiovascular diseases; cardiomyopathy; stroke; ischemia; reperfusion injury; renal reperfusion injury; brain edema; neurotrauma and brain trauma; neurodegenerative disorders; central nervous system disorders; liver disease and nephritis; gastrointestinal conditions; ulcerative diseases; ophthalmic diseases; ophthalmological conditions; glaucoma; acute injury to the eye tissue and ocular traumas; diabetes; diabetic nephropathy; skin-related conditions; viral and bacterial infections; myalgias due to infection; influenza; endotoxic shock; toxic shock syndrome; autoimmune disease; bone resorption diseases; multiple sclerosis; disorders of the female reproductive system; pathological (but non-malignant) conditions, such as hemaginomas, angiofibroma of the nasopharynx, and avascular necrosis of bone; benign and malignant tumors/neoplasia including cancer; leukemia; lymphoma; systemic lupus erthrematosis (SLE); angiogenesis including neoplasia; and metastasis.
TNF is a cytokine produced primarily by activated monocytes and macrophages. Excessive or unregulated TNF production (particularly TNF-α) has been implicated in mediating a number of diseases. It is believed, for example, that TNF can cause or contribute to the effects of inflammation (e.g., rheumatoid arthritis and inflammatory bowel disease), asthma, autoimmune disease, graft rejection, multiple sclerosis, fibrotic diseases, cancer, fever, psoriasis, cardiovascular diseases (e.g., post-ischemic reperfusion injury and congestive heart failure), pulmonary diseases (e.g., hyperoxic alveolar injury), hemorrhage, coagulation, radiation damage, and acute phase responses like those seen with infections and sepsis and during shock (e.g., septic shock and hemodynamic shock). Chronic release of active TNF can cause cachexia and anorexia. And TNF can be lethal.
TNF also has been implicated in infectious diseases. These include, for example, malaria, mycobacterial infection, meningitis. These also include viral infections, such as HIV, influenza virus, and herpes virus, including herpes simplex virus type-1 (HSV-1), herpes simplex virus type-2 (HSV-2), cytomegalovirus (CMV), varicella-zoster virus (VZV), Epstein-Barr virus, human herpesvirus-6 (HHV-6), human herpesvirus-7 (HHV-7), human herpesvirus-8 (HHV-8), pseudorabies and rhinotracheitis, among others.
IL-8 is another pro-inflammatory cytokine, which is produced by mononuclear cells, fibroblasts, endothelial cells, and keratinocytes. This cytokine is associated with conditions including inflammation.
IL-1 is produced by activated monocytes and macrophages, and is involved in inflammatory responses. IL-1 plays a role in many pathophysiological responses, including rheumatoid arthritis, fever, and reduction of bone resorption.
TNF, IL-1, and IL-8 affect a wide variety of cells and tissues, and are important inflammatory mediators of a wide variety of conditions. The inhibition of these cytokines by inhibition of the p38 kinase is beneficial in controlling, reducing, and alleviating many of these disease states.
Various pyrazoles have previously been described:
In U.S. Pat. No. 4,000,281, Beiler and Binon report 4,5-aryl/heteroaryl substituted pyrazoles with antiviral activity against both RNA and DNA viruses, such as myxoviruses, adenoviruses, rhinoviruses, and various viruses of the herpes group.
WIPO Int'l Publ. No. WO 92/19615 (published Nov. 12, 1992) describes pyrazoles as novel fungicides.
In U.S. Pat. No. 3,984,431, Cueremy and Renault report derivatives of pyrazole-5-acetic acid as having anti-inflammatory activity, with [1-isobutyl-3,4-diphenyl-1H-pyrazol-5-yl]acetic acid being specifically described.
In U.S. Pat. No. 3,254,093, Hinsgen et al. report a process for preparing pyrazoles.
WIPO Int'l Publ. No. WO 83/00330 (published Feb. 3, 1983) describes a process for preparing diphenyl-3,4-methyl-5-pyrazole derivatives.
WIPO Int'l Publ. No. WO 95/06036 (published Mar. 2, 1995 reports a process for preparing pyrazole derivatives.
In U.S. Pat. No. 5,589,439, T. Goto, et al. report tetrazole derivatives and their use as herbicides.
EP 515,041 reports pyrimidinyl substituted pyrazole derivatives as novel agricultural fungicides.
Japanese Patent 4,145,081 reports pyrazolecarboxylic acid derivatives as herbicides.
Japanese Patent 5,345,772 reports novel pyrazole derivatives as inhibiting acetylcholinesterase.
Pyrazoles have been reported as useful in treating inflammation.
Japanese Patent 5,017,470 reports synthesis of pyrazole derivatives as anti-inflammatory, anti-rheumatic, anti-bacterial, and anti-viral drugs.
EP 115640 (published Dec. 30, 1983) reports 4-imidazolyl-pyrazole derivatives as inhibitors of thromboxane synthesis, with 3-(4-Isopropyl-1-methylcyclohex-1-yl)-4-(imidazol-1-yl)-1H-pyrazole being specifically described.
WIPO Int'l Publ. No. WO 97/01551 (published Jan. 16, 1997) reports substituted pyrazoles as adenosine antagonists, with 4-(3-Oxo-2,3-dihydropyridazin-6-yl)-3-phenylpyrazole being specifically described.
In U.S. Pat. No. 5,134,142, to Matsuo et al. report 1,5-diaryl pyrazoles as having anti-inflammatory activity.
In U.S. Pat. No. 5,559,137, Adams et al. report pyrazoles (1,3,4,-substituted) as inhibitors of cytokines used in the treatment of cytokine diseases, with 3-(4-fluorophenyl)-1-(4-methylsulfinylphenyl)-4-(4-pyridyl)-5H-pyrazole being specifically described.
WIPO Int'l Publ. No. WO 96/03385 (published Feb. 8, 1996) reports 3,4-substituted pyrazoles as having anti-inflammatory activity, with 3-methylsulfonylphenyl-4-aryl-pyrazoles and 3-aminosulfonylphenyl-4-aryl-pyrazoles being specifically described.
Laszlo et al., Bioorg. Med. Chem. Letters, 8 (1998) 2689-2694, describes certain furans, pyrroles, and pyrazolones, particularly 3-pyridyl-2,5-diaryl-pyrroles, as inhibitors of p38 kinase.
WIPO Int'l Publ. No. WO 98/52940 (PCT Patent Application No. US98/10436 published on Nov. 26, 1998) reports pyrazoles, compositions containing those pyrazoles, and methods for treating p38-mediated disorders using those pyrazoles.
WIPO Int'l Publ. No. WO 00/31063 (PCT Patent Application No. US99/26007 published on Jun. 2, 2000) also reports pyrazoles, compositions containing those pyrazoles, and methods for making pyrazoles.
In view of the importance of pyrazoles in the prevention and treatment of several pathological conditions (particularly those associated with p38 kinase activity, TNF activity, and/or cyclooxygenase-2 activity), there continues to be a need for processes for making substituted pyrazoles. The following disclosure describes such a process.